OBJECTIVES: Fenfluramine and cannabidiol have been approved as add-on therapies to reduce seizures in patients with Dravet syndrome (DS). However, no direct comparative trials between these two drugs are available. Although the dosage of both drugs can be determined based on other concomitant anti-seizure medications or tolerance, irrespective of the severity of DS or potency of therapy, previous research has offered indirect comparisons by comparing each dose to all doses. The aim of network meta-analysis (NMA) in this study is to assess the comparative effectiveness of fenfluramine versus cannabidiol, which are recommended for treating DS by practice guidelines.

METHODS: A systematic literature review was conducted to identify randomized controlled trials (RCTs) of fenfluramine and cannabidiol for treating DS patients. Primary outcomes, placebo-adjusted reductions from baseline in monthly convulsive seizure frequency (MCSF), were extracted from each study of fenfluramine and cannabidiol and pooled, regardless of dosage and concomitant medications such as stiripentol and clobazam. Comparative efficacy of the two drugs was assessed using Bayesian NMA. Mean differences of MCSF along with 95% credible intervals (CrIs) and intervention rankings were presented as a result.

RESULTS: Five relevant placebo-controlled RCTs involving DS patients aged 2-18 years were identified, demonstrating a statistically significant reduction in MCSF compared to placebo. The mean difference in MCSF reduction from baseline between fenfluramine and cannabidiol was 47.1% (95% CrI: 32.2-58.6). Among the three alternatives (fenfluramine, cannabidiol, and placebo), fenfluramine ranked highest in efficacy, with cannabidiol ranked second. Both of fenfluramine and cannabidiol were ranked superior to placebo in terms of efficacy based on Bayesian treatment rankings.

CONCLUSIONS: The NMA indicates that fenfluramine is more efficacious than cannabidiol in the reduction of MCSF. Fenfluramine could be considered as an optimal add-on therapy for drug-resistant epilepsy patients with DS.